1. Field of the Invention
The present invention relates to stabilized, sterilized cyanoacrylate adhesive compositions with the controlled level of high viscosity, methods of making these compositions and to their use for medical applications.
2. Description of Related Art
Cyanoacrylate esters are well known to be adhesives and have been used extensively in different fields due to their quick bonding and applicability to a large range of substrates. They are used as industrial and structural adhesives, consumer product for repair of household items and in the hobby sector for assembly and repair. In addition, cyanoacrylate compositions have found application in medicine for closing wounds especially in cases where suturing does not provide satisfactory results. Cyanoacrylate esters are used in protecting surface injuries including abrasions, lacerations, sores, burns and other open surface wounds. In spite of their interesting properties and wide applications in different fields, cyanoacrylate monomers have disadvantages which prevent use of cyanoacrylates in certain fields. For example, the inherent low viscosity of cyanoacrylate monomers in medical applications may result in the spreading of the adhesive into undesired areas as a consequence of the cyanoacrylate adhesive's runniness. In addition, the runniness of the cyanoacrylate monomer makes it difficult to prevent the adhesive from entering the wound, which will adversely affect the healing of the wound.
In order to obtain a cyanoacrylate adhesive composition with a desired level of higher viscosity, different thickening agents and methods have been employed. Thickening agents, such as polymers have been used to improve the viscosity of the cyanoacrylate adhesive compositions. The polymer additives are soluble in cyanoacrylate compositions either at room or elevated temperature.
Misiak et al., U.S. Pat. Appl. No. 20070092481, disclose a thickened cyanoacrylate adhesive composition by using poly[butyleneterephthalate-co-poly(ethyleneglycol) terephthalate] as a viscosity modifier. The formulation of cyanoacrylate adhesives as low viscosity emulsions, non-flowable and gels forms can be prepared by adding this polymer component to cyanoacrylate compositions. The viscosity of the composition is dependent upon the nature and level of the polymer material used in the composition. Kotzey et al. U.S. Pat. No. 6,797,107 disclose a solid cyanoacrylate adhesive composition which can be applied to a substrate in solid form and which polymerizes into an adhesive polymer upon liquefying. The solid cyanoacrylate composition liquefies at temperatures slightly above room temperature and polymerizes upon liquification. ε-caprolactones are used as a solidifying polymer with cyanoacrylate monomers and other additives to form the solid cyanoacrylate adhesive composition.
Hickey et al. U.S. Pat. No. 6,743,858 disclose a method of making a thickened sterile monomeric adhesive composition Preparation of the composition includes placing a mixture of a polymerizable monomer and a thickening agent in a container, sealing the container and sterilizing the container and the mixture. The thickening agent is soluble in the monomer at room temperature. Suitable thickeners employed include, for example, polyoxalates, lactic-glycolic acid copolymers, polycaprolactone, lactic acid-caprolactone copolymers, poly (caporolactone+DL-lactide+glycolide), polyorthoesters, polyalkyl acrylates, copolymers of alkylacrylate and vinyl acetate, polyalkyl methacrylates, and copolymers of alkyl methacrylates and butadiene.
Shalaby U.S. Pat. No. 6,299,631 discloses a bioabsorbable adhesive/hemostatic formulation of a 2-alkoxyalkylcyanoacrylate with trimethylene carbonate-based polymers as the viscosity thickener.
Greff et al. disclose, in U.S. Pat. No. 5,665,817, alkyl cyanoacrylate compositions suitable for topical application to human skin, which comprise a suitable amount of the thickening agent to increase the viscosity. The thickening agent used is biocompatible materials that increase the viscosity of the alkyl cyanoacrylate composition, which include polymethylmethacrylate (PMMA) or other preformed polymers soluble in the alkyl cyanoacrylate. The thickening agent is added to provide a viscosity of from about 2 to 50,000 centipoises (cp) at 20° C.
Linden et al. U.S. Pat. No. 5,350,789 disclose 2-cyanoacrylate-based tissue adhesives employing biocompatible oxalate polymers as reactive plasticizers and thickening agents. The adhesives are capable of being formulated to allow modulus matching of the adhesive and the substrate.
Leung et al. U.S. Pat. No. 5,328,687 disclose adhesive compositions which contain thickening agents that may be used for bonding tissue. Polymer thickeners employed include polylactic acid, polyglycolic acid, lactic-glycolic acid copolymers, polycaprolactone, lactic acid-caprolactone copolymers, poly-3-hydroxybutyric acid, polyorthoesters, polyalkyl acrylates, copolymers of alkylacrylate and vinyl acetate, polyalkyl methacrylates, and copolymers of alkyl methacrylates and butadiene.
O'Sullivan et al. U.S. Pat. No. 4,038,345 disclose stable cyanoacrylate adhesive compositions having improved viscosities. The adhesive compositions have viscosities in excess of about 500 centipoises comprising at least one monomeric ester of 2-cyanoacrylic acid, and a polyacrylate thickener which is pretreated to have a reduced viscosity greater than about 5 cp. A free radical polymerization initiator is used in the amount of less than about one percent by weight. The composition also contains an inhibitor of the anionic polymerization of the monomer. O'Sullivan discloses a process for preparing improved cyanoacrylates which involves heating a conventional polyacrylate thickener at a suitable temperature and for a suitable period of time to reduce its content of free radical polymerization initiators to below about one percent; and dissolving a sufficient amount of polymer thickener in the adhesive monomer to produce a cyanoacrylate adhesive composition with suitable viscosity.
Gleave discloses in U.S. Pat. No. 4,102,945, a cyanoacrylate adhesive composition thickened by a copolymer or terpolymer resin capable of being dissolved or solvated by the cyanoacrylate monomer exhibits significantly improved peel strength. Polymer thickeners are acrylonitrile-butadiene-styrene terpolymers, methacrylate-butadiene-styrene terpolymers, and vinylidene chloride-acrylonitrile copolymers.
Setsuda et al. U.S. Pat. No. 3,692,752 disclose thickened cyanoacrylate solutions containing certain polyether acrylates/methacrylates, acrylic/methacrylic esters of bis(hydroxyalkyl) phosphonic acid derivatives, and acrylic/methacrylic esters of tris(hydroxyalkyl) cyanuric acid derivatives.
Wicker et al. disclose, in U.S. Pat. No. 3,527,841, 2-cyanoacrylate adhesive compositions for general and particular for surgical uses containing poly (lactic acid) as a viscosity thickener and an acidic compound such as sulfur dioxide and a free radical stabilizer such as hydroquinone.
Wicker U.S. Pat. No. 3,282,773, discloses cyanoacrylate adhesive compositions in which poly (methylmethacrylate) was used as the thickener.
Polymer of cyanoacrylates has also been used to increase the viscosity of the cyanoacrylate adhesive compositions. U.S. Pat. Appl. No. 20060062687 to Morales discloses a method of sterilizing 2-cyanoacrylate compositions with poly-cyanoacrylate as the thickener, including heating the composition in a device at a temperature of from about 70 to about 140° C. for an effective amount of time. Morales discloses sterilized 2-cyanoacrylate ester compositions for use in medicine or surgery. Morales also discloses a method for assaying the sterilization of cyanoacrylate compositions.
U.S. Pat. No. 3,564,078 discloses the use of poly (ethyl 2-cyanoacrylate) as a component of cyanoacrylate compositions. U.S. Pat. No. 3,527,224 to Rabinowitz discloses a surgical adhesive composition comprising monomeric and polymeric n-pentyl cyanoacrylate obtained by free-radical polymerization. U.S. Pat. No 2,794,788 teaches thickening of cyanoacrylate adhesives by dissolving polymeric alkyl cyanoacrylates, as well as other compounds including methacrylates, polyacrylates and cellulose esters.
Organic or inorganic powders, which are not soluble in cyanoacrylate monomer, have also been used as fillers to adjust the viscosity of cyanoacrylate compositions. Such materials include various inert inorganic materials such as silica, quartz, alumina, calcium and metal salts and organic powders such as polycarbonates, polyvinylidene fluorides, polyethylenes, and other polymeric powders. For example, U.S. Pat. No. 4,533,422 discloses cyanoacrylate compositions which employ fumed silicas as the filler are stable and exhibit a high thixotropic ratio. U.S. Pat. No. 3,607,542 discloses the preparation of a water-resistant cyanoacrylate paste containing insoluble, inert fillers such as salts of calcium, titanium, zinc, tin, aluminum, iron and copper, among others. U.S. Pat. No. 4,105,715, discloses the use of finely divided organic powders such as polycarbonates, polyvinylidene fluorides, polyethylenes, and other polymeric powders are proposed as additives for cyanoacrylates. Blending insolvable materials with cyanoacrylate compositions can cause separation while the adhesive is stored, resulting in ineffective modification of the viscosity. Also, the presence of the fillers can sometimes affect the quality of the bonding.
The use of polymer additives to improve the viscosity of cyanoacrylate adhesives presents different disadvantages. Relatively small modification of the viscosity was achieved by using polymer additive as the viscosity modifer. The amount of the polymer thickener is limited due to the poor solubility of certain polymers in the cyanoacrylate monomer so that it was difficult to obtain highly viscous adhesives. Increasing the amount of polymer thickener incorporated would result in spinnability, reduction of optical clarity and weakening of the adhesive bond. In addition, many polymer additives used as the thickener undergo decomposition under sterilization conditions, which lead to the decrease of the viscosity. Such instability becomes more obvious when the cyanoacrylate adhesive compositions are stabilized by acids, due to the fact that those acids destabilize the polymer thickener in the compositions. Curing or further polymerization of the cyanoacrylate adhesive occurs during the process of sterilization even in the presence of certain amounts of stabilizers. Sometimes polymerization induced by the sterilization is so serious that the cyanoacrylate compositions are no longer usable. In other cases, the shelf life of the sterilized cyanoacrylate compositions can be dramatically shorten even though these sterilized adhesive compositions are still usable. Presently, the only acceptable polymer thickener which can be successfully used for commercial cyanoacrylate adhesive compositions include poly(methylmethacrylate) or poly(vinylacetate). Therefore it would be desirable to provide a simple and effective method to prepare cyanoacrylate compositions with the controllable viscosity without sacrificing the shelf life stability of the cyanoacrylate compositions.